The long-term objective of this application is to develop a vaccine capable of inducing protective immune responses in rhesus macaques against pathogenic Simian Immunodeficiency Virus (SIV). For this propose, the well defined rhesus monkey model system will be used to study immune responses generated by coadministration of the cytokine interlukin-12 (IL-12) with an SIV DNA vaccine. It is expected that IL-12 will enhance vaccine induced protective anti-SIV responses by creating an environment required for Type I cell commitment, and by enhancing SIV antigen-specific proliferation of Type-1 cells. The vaccine that will be used in these studies is a construct that contains the DNA sequences of SIVsmB7, a defective virus that expresses gag, env and nef proteins. The defective virus genome was cloned into the pJW4303 expression vector that has been used by other investigators to induce immune responses against SIV in rhesus monkeys. Our hypothesis is that protective immune responses induced by SIVsmB7 DNA vaccination can be enhanced by simultaneous administration of rhesus IL-12. This hypothesis is based on preliminary experiments performed by our laboratory that showed that SIVsmB7 was immunogenic and that monkeys that were inoculated with cells expressing SIVsmB7 had very low to undetectable viral loads after challenge with pathogenic SIVsmE660. To test this hypothesis, groups of 5 rhesus macaques will be inoculated either with the SIVsmB7 DNA expression vector alone or coadministered with IL-12. Induction of humoral and cellular responses to SIVsm antigens will be monitored by SIV-ELISA, neutralizing antibody, CTL assays, and cytokine profile determinations. These responses will be analyzed and compared. We will determine if the immune response elicited by these vaccination strategies will protect animals against pathogenic SIVsmE660 virus challenge. Responses to challenge will be ascertained by measuring virus loads, antibody production, as well as CMI and cytokine responses. Results obtained from these experiments will give important information for the development of an effective vaccine against SIV (and potentially, against HIV).